Bronchodilator expectorant elixir

ABSTRACT

A bronchodilator expectorant composition containing a sympathomimetic amine bronchodilator, the xanthine bronchodilator theophylline, guaiacol or a water soluble form thereof and a sedative.

U.S. Pat. 3,109,773, dated Nov. 5, 1963 of Neil H. Mercer and Robert J.Bequette deals with a bronchodilator-expectorant elixir containingtheophylline in highly concentrated liquid dosage form made possiblethrough the solubilizing effect of glyceryl guaiacolate, or otherwater-soluble form of guaiacol, on the theophylline. Those compositionshave the advantage of providing a therapeutic dose of theophylline andglyceryl guaiacolate or equivalent water soluble form of guaiacol in arelatively small volume of elixir which may contain alcohol insufficient amount to assist in absorption of the theophylline, but ininsufficient amount to interfere with patient acceptance. Thecompositions have solution stability over a wide pH range includingacidic conditions. The latter is desirable since considerably morelatitude is thereby afforded the flavorist in compounding an acceptablyflavored product and because the theophylline remains in solution evenunder the strongly acid conditions met in the stomach, thus reducing thepossiblity of gastric irritation.

The present invention provides the solution to a difficult problemencountered in preparing an elixir of the foregoing type retaining eachof the advantages thereof relative to palatability, absorption,tolerance, and acceptability, but including therein as additional activeingredients a sympathomimetic amine bronchodilator component, such asephedrine hydrochloride, and a barbiturate sedative.

Bronchodilator compositions containing both adrenergic and xanthine-typebronchodilator agents to counteract bronchospasm, and a sedative arewidely used because of their effectiveness, despite the disadvantages ofcertain side effects. The sedative serves the purpose of relieving theanxiety to which patients suffering from bronchial asthma are frequentlysubject and also counteracting the central nervous system stimulatingside effects of the sympathomimetic amines which serves as adrenergicbronchodilator components. Phenobarbital is the most widely usedsedative in such compositions, although other barbiturates have beenused in tablet or capsule dosage forms.

Phenobarbital is generally preferred for such compositions because ofits relatively long duration of action providing a continuous calmingeffect during dosage for chronic conditions. Unfortunately a physicalincompatibility between phenobarbital and theophylline is operant whichresults in their precipitation from solution when it is attempted toincorporate phenobarbital in sedative effective amounts into atheophylline-glyceryl guaiacolate elixir of the type described in U.S.3,109,773. Apparently the phenobarbital interferes with the solubilizingaction of the glyceryl guaiacolate on the theophylline, resulting inprecipitation thereof. Furthermore, the phenobarbital is itself renderedinsoluble. It is thus impossible to formulate a clear solution free frominsoluble suspended ingredients. Solutions are preferred in accordancewith the object of providing rapid and uniform absorption withoutgastric irritation and for convenience and accuracy of administration.The uncertainty of uniform resuspension of insoluble ingredients is anever-present problem in the administration of drugs as liquidsuspensions.

We have found that certain barbiturates form clear solutions whenemployed in combination with theophylline, ephedrine hydrochloride, andglyceryl guaiacolate. The reason for the specific compatibility which wehave discovered is not known since the operability of certainbarbiturates does not appear to be a function of their water or alcoholsolubilities.

There is provided according to the present invention a bronchodilatorexpectorant composition containing a sympathomimetic aminebronchodilator such as ephedrine, pseudophedrine, methoxyphenamine, orprotokylol or an acid addition salt thereof; the xanthine bronchodilatortheophylline; glyceryl guaiacolate, or a water soluble form thereof suchas guaiacol itself, or potassium guaiacol sulfonate; and a sedativecomponent, cyclopal, aprobarbital, butabarbital, or pentobarbital. Theseingredients are contained in an aqueous alcoholic vehicle to providefinal composition which contains at least 40% by volume of water and upto 20% by volume of ethanol, which shares the advantage of pH stability,palatability, freedom from gastric irritation, and effective absorptionwith the compositions of U.S. 3,109,773.

The compositions are designed to contain a therapeutically effectivedosage of each active ingredient in a dosage volume of up to 2tablespoons (30 ml.) of elixir. Each 5 ml. unit contains from about 1/6up to a full therapeutic dose of each ingredient, or more particularlyfrom 16.6 to 175 mg. of theophylline; from 7.5 to 350 mg. of glycerylguaiacolate, or an equivalent solubilizing weight of potassium guaiacolsulfonate or guaiacol; from 4 to 25 mg. of ephedrine hydrochloride,ephedrine sulfate, or a pharmacologically equivalent amount of one ofthe previously mentioned sympathomimetic bronchodilators; from 2 to 35mg. of one of the barbiturates listed above, preferably butabarbital.For the latter, concentrations in the range of 2 to 15 mg./5 ml. areemployed. A soluble form of ephedrine, pseudoephedrine,methoxyphenamine, or protokylol is, of course, used. Ephedrine sulfateand ephedrine hydrochloride may be used interchangeably in the amountspecified. The concentrations of other adrenergic bronchodilators foruse in the present elixirs are adjusted in accordance with accepteddosage practice for each drug.

In its broadest concept, the present bronchodilator expectorantcompositions are clear aqueous or aqueous-alcoholic solutions containingat least 40% by volume of water and up to 20% by volume of alcohol, andhaving dissolved therein 0.83 g. to 4.37 g. of theophylline per 100 ml.of water in the composition, sufficient guaiacol or pharmaceuticallyacceptable water soluble form thereof to serve as solubilizer for thetheophylline, a pharmacologically effective dose of a sympathomimeticbronchodilator, and a sedative dose of a barbiturate selected from5-allyl-5-cyclopentenylbarbituric acid (cyclopal),5-allyl-5-isopropylbarbituric acid (aprobarbital),5-ethyl-5-(2-butyl)barbituric acid (butabarbital), and5-ethyl-5-(2-pentyl)barbituric acid (pentobarbital).

The foregoing concentration range of theophylline exceeds that of asaturated solution thereof in the solvents selected as vehicles in thisinvention. It is solubilized in accordance with the invention set forthin U.S. 3,109,773. The aforementioned barbiturates in the concentrationsgiven, in company with the sympathomimetic amine ingredient, are solublein the composition and surprisingly do not themselves precipitate norcause precipitation of the theophylline. In order to illustrate thespecificity required of the barbiturate for use in the presentcompositions, the following experiment is described.

EXAMPLE

Stock solutions as follows were prepared.

    ______________________________________                                        Solution No. 1-Syrup base                                                     Ingredient:    Amount/500 ml. of solution                                     ______________________________________                                        Theophylline          g        5.1                                            Glyceryl guaiacolate  g        3.0                                            Sucrose               g        250.0                                          Sodium saccharin      g        0.5                                            Sodium cyclamate      g        3.0                                            70% sorbitol solution ml       25.0                                           Citric acid           g        2.0                                            Sodium Citrate        g        1.5                                            Distilled water, q.s. ml       400                                            Solution No.2.-Alcohol solution                                               Methylparaben         g        0.6                                            Propylbaraben         g        0.15                                           Ethyl vanillin        g        0.10                                           Menthol (4% in ethanol)                                                                             ml       0.08                                           Grenadine flavor      ml       0.04                                           Ethyl alcohol         ml       78.95                                          Solution No.3.-Ephedrine hydrochloride solution                               Ephedrine hydrochloride                                                                             g        0.8                                            Distilled water q.s.  ml       10.0                                           ______________________________________                                    

The amounts of barbiturates specified in the following list were thenweighed and dissolved in a 79 ml. portion of the alcohol solution(Solution No. 2). This was then mixed with 400 ml. of Solution No. 1 and10 ml. of Solution No. 3 was added thereto. The mixture was then dilutedto 500 ml. with distilled water. In some instances the ingredients didnot dissolve and stability studies were

    ______________________________________                                                            Con-                                                                  A-      centra-                                                               mount   tion                                                                  used    per                                                                   per     15 ml.                                                    Barbituric acid                                                                           500 ml. elixir                                                    derivative  (g.)    (mg.)   Stability result                                  ______________________________________                                        5,5-diethyl-                                                                              9.9     300     1                                                  (barbital).                                                                  5-allyl-5-(2-pentyl)-                                                                     3.3     100     1                                                  (secobarbital                                                                5-ethyl-5-isoamyl-                                                                        1.65    50      Precipitation occurred                             (amobarbital).              within 1 wk.                                     5-ethyl-5-n-butyl-                                                                        3.3     100     1                                                  (butothal)                                                                   5-ethyl-methyl-5-                                                                         1.98    60      1                                                  phenyl                                                                        (mephobarbital).                                                             5-ethyl-5-(2-butyl)-                                                                      0.99    30      Solution clear after 4 wks.                        (butabarbital).             storage at room temp.                                                         crystallization occurred                                                      at 0° C. after 4 wks.                     5,5-diallyl 0.99    30      Solution remained clear                                                        for 1 wk. but slight                                                          crystallization occurred                                                      both at room temp. and                                                        at 0° C. after 4 wks.                     5-allyl-5-cyclopent-                                                                      3.3     100     Solution remained clear                            1-onyl(cyclopal).           at room temp. for 4                                                           wks., but light crystalli-                                                    zation occurred at 0° C.                  5-allyl-5-isobutyl-                                                                       6.6     200     1                                                  (itobarbital)                                                                5-allyl-5-isopropyl-                                                                      1.98    60      Solution remained clear                            (aprobarbital).              at room temp. for 4 wks.                                                     but slight crystalliza-                                                       tion occurred at 0° C.                                                 after 4 wks., but not                                                         after 1 wk.                                      5-allyl-5-phenyl-                                                                         0.6     200     1                                                  (alphenyl).                                                                  ______________________________________                                         1 clear solution failed to form on mixing the ingredients, and no             stability studies were therefore initiated.   not then initiated with suc     sample. The solutions which formed satisfactorily were filtered to remove     any foreign material, and put aside and stored in paired lots at 0°     C. and at room temperature. They were examined after 4 weeks for     crystallization.

In the preceding table there are identified the various barbituratestested, the amounts used, and the dose thereof contained in 15 ml. ofthe final composition, to which the amount employed corresponds. In eachinstance this dose is a sedative dose of the barbiturate as specified ineither the Merck Index. U.S.P. XVI, NF X or NF XI.

It is apparent from the foregoing that the results obtained withcyclopal, aprobarbital, and butabarbital are truly unexpected in view ofthe similarity of the chemical structures properties of these substancesto closely related barbiturates which were found to be unsatisfactory.Refer, for instance, to itobarital, diallylbarbituric acid,secobarbital, barbital, butethal, and the 5-phenyl barbiturates.Pentobarbital at a concentration of 10 mg./15 ml. provided a clearsolution of the composition given in the foregoing example. Thisconcentration of pentobarbital is slightly less than a sedative dose(the recommended dose is 30-500 mg.) Stable clear solutions having asedative dose of 15 mg. of pentobarbital per 15 ml. of elixir can,however, be formulated as outlined above.

Attempts were made to formulate elixirs as described in the foregoingexample using various concentrations of the barbiturates listed below.They proved to be unsatisfactory for failure to form clear solutionscontaining effective sedative amounts in volumes of 5-30 ml. of theelixir.

5-allyl-5-ethylbarbituric acid

5-methyl-5-phenylbarbituric acid

5-cyclohex-1-enyl-1,5-dimethylbarbituric acid (hexobarbital)

5-cyclohex-1-enyl-5-ethylbarbituric acid (cyclobarbital)

5-ethyl-5-phenylbarbituric acid (phenobarbital)

What is claimed is:
 1. A bronchodilator-expectorant compositioncomprised of a solution containing at least 40% by volume of water andcharacterized by containing in each 5 milliliters thereof 16.6 to 175mg. of theophylline, 7.5 to 350 mg. of glyceryl guaiacolate or anequivalent solubilizing weight of potassium guaiacol sulfonate orguaiacol, and from 1/6 to a full therapeutic dose of ephedrine,pseudoephedrine, methoxyphenamine, or protokylol, and from 2 to 35 mg.of cyclopal, aprobarbital, butabarbital, or pentobarbital .[...]..Iadd.wherein the amount of theophylline dissolved in said solutionexceeds the saturated solution amount thereof in the solvents employedin said solution, and the theophylline in solution which exceeds saidsaturated solution amount is solubilized and held in solution by saidglyceryl guaiacolate or equivalent solubilizing weight of potassiumguaiacol sulfonate or guaiacol. .Iaddend.
 2. The composition of claim 1containing up to 20% by volume of alcohol.
 3. The composition of claim 1containing 4 to 25 mg. of ephedrine hydrochloride or ephedrine sulfateand from 2 to 15 mg. of butabarbital per 5 milliliters of elixir.